The present invention relates to novel formulations, and to their use in the treatment and/or prophylaxis of certain disorders.
[R-(Z)]-xcex1-(methoxyimino)-xcex1-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrile monohydrochloride (compound X) and methods for its preparation are disclosed in EP-A-0392803, WO95/31456 and WO93/17018. The compound enhances acetylcholine function via an action at muscarinic receptors within the central nervous system, and is therefore of potential use in the treatment and/or prophylaxis of dementia in mammals.
WO96/12486 discloses the use of compound X in the manufacture of a medicament for enhancing amyloid precursor protein processing along a non-amyloidogenic pathway in patients suffering from, or at risk of developing, Alzheimer""s disease.
Fast-release swallow tablet and oral solution formulations of compound X both result in rapid absorption of the compound into the circulation, and require twice a day dosing for optimal efficacy.
It has now been surprisingly found that it is possible to formulate compound X, which has very high water solubility and is active at extremely low doses, in such a way that release is controlled to take place over a period of hours. Such a formulation would require dosing only once a day: this is likely to improve compliance in a patient population characterised by poor memory; it may also reduce side-effects in case of accidental overdosing.
Accordingly, in a first aspect the present invention provides a controlled release oral dosage form containing 0.04% w/w pfb compound X and 98.5-99.5% w/w total mono, di and triglycerides and polyethylene glycol mono and diesters consisting of Gelucire 50/13 (EP) and Gelucire 50/02 (Fr Ph) in a ratio of  greater than 0.02 Gelucire 50/13 (EP) to Gelucire 50/02 (Fr Ph), in a hard gelatin capsule containing 0.10 mg/capsule compound X pfb, such that the release profile of the capsule in 1 mM HCl is 20-60% after 8 hr.
Preferably the release profile after 8 hr is 20-40% or 30-60%.
Gelucire 50/13 (EP) is a mixture of mono, di and triglycerides and polyethylene glycol mono and diesters specified in the European Pharmacopeia xe2x80x9cStearoyl Macroglyceridesxe2x80x9d (Supplement 1998) as:
specific mixtures of monoesters, diesters and triesters of glycerol and monoesters and diesters of macrogols with a mean relative molecular mass between 300 and 4000 comprising:
free glycerol content:  less than 3%
lauric acid (C12):  less than 5%
myristic acid (C14):  less than 5%
different nominal amounts of stearic acid (C18) and of palmitic acid (C16). The sum of stearic acid and of palmitic acid is not less than 90%.
Gelucire 50/02 (Fr Ph) is a mixture of mono, di and triglycerides and polyethylene glycol mono and diesters specified in the French Pharmacopoeia xe2x80x9cGlycerides Polyglycolyses Saturesxe2x80x9d (1990) as:
specific mixtures of mono, di and triglycerides and polyethylene glycol mono and diesters, obtained either by partial alcoholysis of hydrogenated vegetable oils using polyethylene glycol of relative molecular weight ranging 200-2000, or by esterification of saturated fatty acids using polyethylene glycol of relative molecular weight ranging 200-2000, comprising:
free glycerol content:  less than 3%
caprylic acid (C8):  less than 15%
capric acid (C10):  less than 15%
lauric acid (C12):  less than 50%
myristic acid (C14):  less than 25%
palmitic acid (C16):  less than 55%
stearic acid (C18):  less than 97%
The mono, di and triglycerides and polyethylene glycol mono and diesters preferably make up 99.41% of the dosage form. The ratio of Gelucire 50/13 (EP) to Gelucire 50/02 (Fr Ph) is preferably  less than 0.055, more preferably xe2x89xa60.053.
In a preferred aspect the mixture of mono, di and triglycerides and polyethylene glycol mono and diesters consists of Gelucire 50/13 (Gattefosse) and Gelucire 50/02 (Gattefosse). Most preferably the composition comprises 97.41% Gelucire 50/13 (Gattefosse) and 2.00% Gelucire 50/02 (Gattefosse) or 94.41% Gelucire 50/13 (Gattefosse) and 5.00% Gelucire 50/02 (Gattefosse).
The composition preferably additionally comprises propylene glycol, preferably at 0.45% w/w (1.13 mg/capsule).
The composition preferably additionally comprises 3,4,5-trihydroxybenzoic acid propyl ester, preferably at 0.10% w/w (0.25 mg/capsule).
In a preferred embodiment of the first aspect the composition is selected from:
in a hard gelatin capsule.
In a second aspect, the present invention provides a controlled release oral dosage form containing compound X of the following composition:
granulated, compressed into tablets and coated to a 3% weight gain with a seal coat consisting of a solution of hydroxypropyl methylcellulose aqueous dispersion with plasticizer in purified water at 10% solids followed by a coat consisting of ethylcellulose aqueous dispersion with oleic acid, ammonium hydroxide and plasticizer or a mixture of ethylcellulose aqueous dispersion with oleic acid, ammonium hydroxide and plasticizer and hydroxypropylmethylcellulose aqueous dispersion with polytheylene glycol plasticizer, such that 40-65% of the drug is released within 8 hours in water.
The composition preferably additionally comprises: sodium dihydrogen citrate, preferably at a level of 1.50 mg/tablet (1.0%) and/or magnesium stearate, preferably at a level of 1.125 mg/tablet (0.75%).
In preferred embodiments of the second aspect:
hydroxpropyl methylcellulose is Methocel E4M CR;
microcrystalline cellulose (nominal mean particle size 50 microns) is Avicel PH101;
microcrystalline cellulose (nominal mean particle size 100 microns) is Avicel PH102;
hydroxypropyl methylcellulose aqueous dispersion has polyethylene glycol plasticizer and is preferably Opadry White or Opadry Clear (YS-1-9025A); and/or ethylcellulose aqueous dispersion has fractionated coconut oil plasticizer and is preferably Surelease Clear (E-7-19010).
In a third aspect, the present invention provides a controlled release oral dosage form containing compound X of the following composition:
compressed into tablets and coated to a 3% weight gain with a seal coating solution consisting of hydroxymethylcellulose aqueous dispersion with plasticizer in purified water at 10% solids concentration followed by a coat consisting of ethylcellulose aqueous dispersion with oleic acid, ammonium hydroxide and plasticizer or a mixture of ethylcellulose aqueous dispersion with oleic acid, ammonium hydroxide and and hydroxypropylmethylcellulose aqueous dispersion with plasticizer.
In one preferred embodiment of the third aspect the composition additionally comprises sodium dihydrogen citrate, preferably at a level of 3.00 mg/tablet (2.0%) and/or colloidal silicon dioxide, preferably at a level of 0.75 mg/tablet (0.50%) and/or magnesium stearate, preferably at a level of 1.125 mg/tablet (0.75%) and/or the microcrystalline cellulose has a mean particle size of 100 microns, preferably at a level of 32.5 mg/tablet (21.7%); and coated to a 3% weight gain with a seal coating solution consisting of hydroxymethylcellulose aqueous dispersion with plasticizer in purified water at 10% solids concentration followed by a coat consisting of ethylcellulose aqueous dispersion with oleic acid, ammonium hydroxide and plasticizer or a mixture of ethylcellulose aqueous dispersion with oleic acid, ammonium hydroxide and plasticizer and hydroxypropylmethylcellulose aqueous dispersion with polytheylene glycol plasticizer, such that 35-50% of the drug is released within 8 hours in water.
In a second preferred embodiment of the third aspect the composition is wet granulated before compression using an ethyl cellulose aqueous dispersion containing oleic acid, ammonium hydroxide and plasticizer, preferably at a level of 7.5-15.0 mg/tablet (5.0-10.0%). Where the composition is wet granulated, it additionally comprises sodium dihydrogen citrate, preferably at a level of 1.50 mg/tablet (1.0%), and/or magnesium stearate, preferably at a level of 1.25 mg/tablet (0.75%), and/or the micorcrystalline cellulose has a mean particle size of 50 microns, preferably at a level of 37.5 mg/tablet (25%); and coated to a 3% weight gain with a seal coating solution consisting of hydroxymethylcellulose aqueous dispersion with plasticizer in purified water at 10% solids concentration followed by a coat consisting of ethylcellulose aqueous dispersion with oleic acid, ammonium hydroxide and plasticizer or a mixture of ethylcellulose aqueous dispersion with oleic acid, ammonium hydroxide and plasticizer and hydroxypropylmethylcellulose aqueous dispersion with plasticizer such that 60-75% of the drug is released within 8 hours in water.
In preferred embodiments of the third aspect:
ethylcellulose is Ethocel Std 7;
microcrystalline cellulose (nominal mean particle size 50 microns) is Avicel PH101;
microcrystalline cellulose (nominal mean particle size 100 microns) is Avicel PH102;
hydroxypropyl methylcellulose aqueous dispersion has polyethylene glycol plasticizer and is preferably Opadry Clear (YS-1-9025A); and/or
ethylcellulose aqueous dispersion has fractionated coconut oil plasticizer and is preferably Surelease Clear (E-7-19010).
By controlled release is meant release of the active substance from the dosage form is modified to occur at a slower rate than that from an immediate release product, such as a conventional swallow tablet or capsule.
The dosage form of the invention may be used in the treatment and/or prophylaxis of dementia, including Alzheimer""s disease, in mammals, and/or for enhancing amyloid precursor protein processing along a non-amyloidogenic pathway in patients suffering from, or at risk of developing, Alzheimer""s disease. These disorders are herein after referred to as xe2x80x9cthe Disordersxe2x80x9d.
The present invention provides a method of treating xe2x80x9cthe Disordersxe2x80x9d by administering an effective amount of the controlled release oral dosage form of the invention to a sufferer in need thereof.
The present invention further provides the use of a controlled release oral dosage form of the invention in the manufacture of a medicament for treating xe2x80x9cthe Disordersxe2x80x9d.
The present invention also provides a pharmaceutical composition for use in the treatment of xe2x80x9cthe Disordersxe2x80x9d which comprises a controlled release oral dosage form of the invention.